# Regulation of vascular smooth muscle cell function in atherosclerosis

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $532,993

## Abstract

ABSTRACT Regulation of vascular smooth muscle cells (VSMC) phenotype and function plays important
roles in the pathogenesis of atherosclerosis. Vascular calcification is a characteristic feature of atherosclerosis
that predicts adverse cardiovascular outcome of atherosclerotic patients. Over the last two decades, increasing
studies have demonstrated that vascular calcification is a regulated process; and osteogenic differentiation and
calcification of VSMC contributes significantly to the development of vascular calcification. Calcium signaling is
critical in regulating VSMC function. However, the role of the key intracellular calcium signaling mediator,
phospholipase Cγ (PLCγ), in regulating VSMC calcification is entirely unknown. Our preliminary studies
demonstrated that deletion of PLCγ2 markedly increased calcification in VSMC and in atherosclerotic lesions
of ApoE-/- mice. Using VSMC from PLCγ2 deletion mice (PLCγ2-/-), we determined a direct effect of PLCγ2
deficiency on promoting VSMC calcification, which was independent of the PLCγ1 isoform or the known PLCγ-
mediated signaling pathways, supporting a unique and novel function of PLCγ2 in regulating VSMC
calcification. PLCγ2 deletion in VSMC altered cytoskeleton structure and increased secretion of matrix vesicles
(MVs), membrane-bound nanoparticles that harbor calcium and matrix proteins. MV secretion is a key cellular
event in osteogenesis that initiates extracellular matrix calcification during bone formation; and has recently
been shown to play an important role in vascular calcification. However, the molecular regulations of MV
secretion in VSMC are poorly understood. We found that restoring PLCγ2 normalized MV secretion and
inhibited calcification of the PLCγ2-/- VSMC. Furthermore, PLCγ2 interacted with membrane-associated
filamentous proteins, septin 4/5, which have been shown to dynamically interact with membrane phospholipids
and exocytosis machinery proteins that regulate cytoskeleton arrangement and synaptic vesicle secretion. The
roles of septins in VSMC MV secretion are unknown, our findings of PLCγ2/septin4/5 interactions and
increased septin 4/5 in MVs from PLCγ2-/- VSMC support a new role of septins in regulating VSMC MV
secretion and calcification. Therefore, we hypothesize that PLCγ2 deficiency induces VSMC calcification
via altered septin/actin-cytoskeleton structure that leads to increased MV secretion. With our new
mouse models, Aim 1 will determine the function of SMC-specific PLCγ2 in regulating vascular function in vivo;
and Aim 2 will elucidate the molecular mechanisms underlying PLCγ2-regulated VSMC calcification. These
studies will elucidate an integrative role of SMC-derived PLCγ2 in regulating cytoskeleton structure and MV
secretion that lead to VSMC calcification. PLCγ2 mutations in humans have recently been identified to cause
immunological diseases but the underlying mechanisms are not fully understood. Therefore, delineating the
novel function and mechanism...

## Key facts

- **NIH application ID:** 9964525
- **Project number:** 5R01HL136165-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Yabing Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $532,993
- **Award type:** 5
- **Project period:** 2017-07-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964525

## Citation

> US National Institutes of Health, RePORTER application 9964525, Regulation of vascular smooth muscle cell function in atherosclerosis (5R01HL136165-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9964525. Licensed CC0.

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